The preparation of angiotensin converting enzyme inhibitors such as fosinopril involves a complicated series of steps. The stereospecificity of the intermediate products is very important and often difficult to control. One set of the series of steps used to synthesize involves the conversion of N-benzoyl-trans-4-hydroxy-L-proline methyl ester (See A below) to cis-mesylate methyl ester (See B below), via the following lactonization process: ##STR1## The mesylate (C) is a useful intermediate to fosinopril. However, the process requires several steps and is difficult. Using several steps could lead to poor control of the stereochemical integrity of the mesylate acid resulting in cis and trans epimers being formed. Poor stereochemical control creates a substantial problem since a subsequent Friedal-Crafts alkylation also proceeds with inversion. Inefficiency in either step could ultimately lead to cyclohexyl isomers of fosinopril sodium and subsequent purification problems.
An attempt was therefore made to simplify the procedure using the Mitsunobu process as taught in Synthesis (1981) p 1-28. However, the conventional Mitsunobu process proved too cumbersome to be of commercial value. The process has been modified to better meet the needs of a commercial application.
The invention provides for the coupling of a hydroxy proline derivative with a sulfonic acid by preparing an ammonium sulfonate in situ, instead of utilizing a discrete preparation of a zinc sulfonate. This eliminates one step of the Mitsunobu process as taught by Galynker and Still in Tetrahedron Letters (1982), Vol. 23, No. 43, pp 4461-4464. Also the majority of the reagent by-products can now be removed by filtration because, unexpectedly, a 1:1 by-product complex forms and crystallizes upon partial acidification. This eliminates the cumbersome chromotagraphy process generally required. Consequently, the new process simplifies the purification procedure tremendously.